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The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma

Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downst...

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Autores principales: Canovas Nunes, Sara, Manzoni, Martina, Pizzi, Marco, Mandato, Elisa, Carrino, Marilena, Quotti Tubi, Laura, Zambello, Renato, Adami, Fausto, Visentin, Andrea, Barilà, Gregorio, Trentin, Livio, Manni, Sabrina, Neri, Antonino, Semenzato, Gianpietro, Piazza, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811530/
https://www.ncbi.nlm.nih.gov/pubmed/29440639
http://dx.doi.org/10.1038/s41408-018-0053-z
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author Canovas Nunes, Sara
Manzoni, Martina
Pizzi, Marco
Mandato, Elisa
Carrino, Marilena
Quotti Tubi, Laura
Zambello, Renato
Adami, Fausto
Visentin, Andrea
Barilà, Gregorio
Trentin, Livio
Manni, Sabrina
Neri, Antonino
Semenzato, Gianpietro
Piazza, Francesco
author_facet Canovas Nunes, Sara
Manzoni, Martina
Pizzi, Marco
Mandato, Elisa
Carrino, Marilena
Quotti Tubi, Laura
Zambello, Renato
Adami, Fausto
Visentin, Andrea
Barilà, Gregorio
Trentin, Livio
Manni, Sabrina
Neri, Antonino
Semenzato, Gianpietro
Piazza, Francesco
author_sort Canovas Nunes, Sara
collection PubMed
description Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downstream of its receptor, leading to the activation of the JAK/STAT pathway. The atypical GTPase RhoU lays downstream of STAT3 transcription factor and could be responsible for mediating its effects on cytoskeleton dynamics. Here we demonstrate that RHOU is heterogeneously expressed in primary multiple myeloma cells and significantly modulated with disease progression. At the mRNA level, RHOU expression in myeloma patients correlated with the expression of STAT3 and its targets MIR21 and SOCS3. Also, IL-6 stimulation of human myeloma cell lines up-regulated RHOU through STAT3 activation. On the other hand, RhoU silencing led to a decrease in cell migration with the accumulation of actin stress fibers, together with a decrease in cyclin D2 expression and in cell cycle progression. Furthermore, we found that even though lenalidomide positively regulated RhoU expression leading to higher cell migration rates, it actually led to cell cycle arrest probably through a p21 dependent mechanism. Lenalidomide treatment in combination with RhoU silencing determined a loss of cytoskeletal organization inhibiting cell migration, and a further increase in the percentage of cells in a resting phase. These results unravel a role for RhoU not only in regulating the migratory features of malignant plasma cells, but also in controlling cell cycle progression.
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spelling pubmed-58115302018-02-14 The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma Canovas Nunes, Sara Manzoni, Martina Pizzi, Marco Mandato, Elisa Carrino, Marilena Quotti Tubi, Laura Zambello, Renato Adami, Fausto Visentin, Andrea Barilà, Gregorio Trentin, Livio Manni, Sabrina Neri, Antonino Semenzato, Gianpietro Piazza, Francesco Blood Cancer J Article Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downstream of its receptor, leading to the activation of the JAK/STAT pathway. The atypical GTPase RhoU lays downstream of STAT3 transcription factor and could be responsible for mediating its effects on cytoskeleton dynamics. Here we demonstrate that RHOU is heterogeneously expressed in primary multiple myeloma cells and significantly modulated with disease progression. At the mRNA level, RHOU expression in myeloma patients correlated with the expression of STAT3 and its targets MIR21 and SOCS3. Also, IL-6 stimulation of human myeloma cell lines up-regulated RHOU through STAT3 activation. On the other hand, RhoU silencing led to a decrease in cell migration with the accumulation of actin stress fibers, together with a decrease in cyclin D2 expression and in cell cycle progression. Furthermore, we found that even though lenalidomide positively regulated RhoU expression leading to higher cell migration rates, it actually led to cell cycle arrest probably through a p21 dependent mechanism. Lenalidomide treatment in combination with RhoU silencing determined a loss of cytoskeletal organization inhibiting cell migration, and a further increase in the percentage of cells in a resting phase. These results unravel a role for RhoU not only in regulating the migratory features of malignant plasma cells, but also in controlling cell cycle progression. Nature Publishing Group UK 2018-02-13 /pmc/articles/PMC5811530/ /pubmed/29440639 http://dx.doi.org/10.1038/s41408-018-0053-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Canovas Nunes, Sara
Manzoni, Martina
Pizzi, Marco
Mandato, Elisa
Carrino, Marilena
Quotti Tubi, Laura
Zambello, Renato
Adami, Fausto
Visentin, Andrea
Barilà, Gregorio
Trentin, Livio
Manni, Sabrina
Neri, Antonino
Semenzato, Gianpietro
Piazza, Francesco
The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma
title The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma
title_full The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma
title_fullStr The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma
title_full_unstemmed The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma
title_short The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma
title_sort small gtpase rhou lays downstream of jak/stat signaling and mediates cell migration in multiple myeloma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811530/
https://www.ncbi.nlm.nih.gov/pubmed/29440639
http://dx.doi.org/10.1038/s41408-018-0053-z
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